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Deciphering the secrets of DNA condensation


Department of Physics

About the Project

DNA molecules repel each other in water because they contain a high density of negative charges. However, this electrostatic repulsion is reverted to an attractive force in the presence of multivalent cations which can promote DNA condensation. Theoretical studies suggest that in the presence of divalent ions, dsDNA-dsDNA pairing is facilitated by the alignment of ion hot-spots at the interface between the two strands. Consequently, we hypothesise that sequence homology between the pairing strands is especially convenient for driving condensation, as it may promote optimal matching between the two interacting structures. However, the detailed mechanism by which DNA molecules form these ion hot-spots and condense is largely unknown at the structural level, due to the complexity of interrogating long, flexible DNA molecules at the atomic scale.
Though the mechanism by which homologous fragments in chromosomes preferentially associate with each other without the apparent help of other biomolecules is unknown, its role in cellular function is well-documented. Protein-independent pairing of homologous double-stranded DNA molecules is associated with many important biological processes including the alignment of homologous chromosomes in early meiosis, monoallelic gene expression in mammals, and somatic pairing of homologous chromosomes in Drosophila. In addition, polycation-based DNA condensation is relevant for protecting and carrying foreign genetic material through the human body during gene therapy, which allows us to treat numerous gene-associated human diseases by altering specific gene expressions in pathological cells.
We have demonstrated that we can characterize the structure of DNA with base-pair resolution, using atomic force microscopy (AFM) and all-atom molecular dynamics simulations (MDS) with extremely strong convergence. Our previous studies have provided a comprehensive description of supercoiled DNA (1) and shown preliminary evidence of dsDNA-dsDNA homology pairing. In this project, we propose to determine under what conditions DNA homology pairing is observed, so we will:
1) Determine for what sequences DNA pairing is observed using recently established protocols adapted for standard MDS packages in AMBER
2) Characterise the underlying free energy landscape for the different pairing conditions described above
3) Analyse single-molecule AFM imaging of homologous pairing and compare to predictions made by MDS, to definitively define under which conditions homologous pairing of DNA segments is observed
This project will allow us to understand the mechanisms of DNA condensation in biological systems, and how this effect may be controlled by ionic conditions.
1. ALB Pyne, A Noy, K Main, V Velasco-Berrelleza, MM Piperakis, LA Mitchenall, FM Cugliandolo, JG Beton, CEM Stevenson, BW Hoogenboom, AD Bates, A Maxwell, SA Harris (2020). “Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and recognition” Nat Comms, accepted. https://doi.org/10.1101/863423
References
Informal enquiries should be made to either Dr Agnes Noy () or Dr. Alice Pyne ().

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